There have been many attempts in the medical field to control drug release and maintain drug concentration in the blood at an appropriate level for a long period of time. In order to maintain drug concentration in the blood at an appropriate level for a long period of time, it is necessary for maintaining the absorption of drugs for a long time to use the pharmaceutical ingenuities (sustained-release techniques). Orally administered solid preparations are moved from the upper part of the gastrointestinal tract (the stomach and upper small intestine) to the lower part (the lower small intestine and large intestine) as time passes; the capability of drug absorption is often less in the lower part of the gastrointestinal tract than in the upper part. Therefore, it is considered most important to develop a strategy by which the drug can be continuously absorbed in the lower gastrointestinal tract, in which the solid preparation remains for the longest time.
Known sustained-release techniques include, for example, a sustained-release technique based on diffusion control, i.e., membrane-coated preparations in which core compositions or core tablets that contain drugs are coated with water-insoluble polymer films; matrix preparations produced together with water-insoluble polymers, waxes, etc.; and the like. However, with these techniques, since the release rate of the drug decreases as the release progresses, the drug release rate is deficient in the lower gastrointestinal tract, to which the preparation reaches several hours after administration. As a result, the drug concentration in the blood is hard to maintain.
Another known sustained-release technique adopts the pharmaceutical approach designed to release the drug in the lower gastrointestinal tract (e.g., enteric coated preparations in which immediate release core compositions containing drugs are coated with enteric films). However, this technique controls the drug release with films, and hence requires a film-coating procedure. As a result, the production process of the pharmaceutical preparation becomes complicated.
On the other hand, sustained-release matrix preparations are known that are produced using methacrylic acid-based enteric polymers. The enteric polymer becomes an insoluble substance at a lower pH range than the pH at which the enteric polymer can be dissolved, and becomes a soluble substance at a higher pH range than the pH at which the enteric polymer can be dissolved. Therefore, the enteric polymer-containing matrix preparation can suppress drug release in the upper gastrointestinal tract and rapidly release the drug in the lower gastrointestinal tract. In other words, sensitive pH response of the enteric polymer enables the provision of sustained-release preparations with precisely controlled drug release.
For example, Patent Documents 1, 2, 3, and 4 disclose enteric polymer-containing matrix preparations obtained by mixing an enteric polymer and a drug, followed by a compaction (tablet compression). However, although drug release from matrix preparations is generally considered to be dependent on the surface area of the pharmaceutical preparation, such matrix preparations obtained by tablet compression have a small surface area in contact with a solvent. For poorly soluble drugs with a slow dissolution rate, the small surface area of the pharmaceutical preparation induces deficiency in drug release.
In contrast, Patent Document 5 discloses preparations obtained by wet-kneading a mixed powder containing methacrylic acid copolymer S with ethanol, followed by extrusion. This preparation is formed into sustained-release pellets through wet-kneading and extrusion. Such a preparation (pellets, granules, and powder are referred to as multiple-unit type preparations) can have a larger surface area and is also applicable to poorly-soluble drugs. Furthermore, as compared with single-unit type preparations such as tablets obtained by tablet compression, multiple-unit type preparations like pellets are moderately dispersed in the gastrointestinal tract. Therefore, such pellets can reduce inter-subject variance in drug absorption rather than the tablets.
Moreover, Non-Patent Document 1 discloses multiple-unit type preparations comprised of methacrylic acid copolymer S, methacrylic acid copolymer LD, a drug, polyvinylpyrrolidone, and triethyl citrate, as a plasticizer. The preparations are obtained by wet-kneading with water, and followed by extrusion and spheronization.
Patent Document 1: Japanese Examined Patent Publication No. 1992-43049
Patent Document 2: Japanese Unexamined Patent Publication No. 1994-199657
Patent Document 3: U.S. Pat. No. 4,968,508
Patent Document 4: US Patent Publication No. 2006-0159753
Patent Document 5: Japanese Unexamined Patent Publication No. 1994-24991
Non-Patent Document 1: International Journal of Pharmaceutics, 2001, Vol. 213, p. 7-12